Title: Immune responses to the erythrocytic stage of Plasmodium falciparum and the development of vaccines against malaria
PhD Student: Kelwalin Dhanasarnsombut
Supervisors: Dr. David Cavanagh (University of Edinburgh, United Kingdom) and Prof. Anthony Holder (National Institut for Medical Research, United Kingdom)
Collaborators: Dr. Alison Creasey and Dr. Mike Blackman (University of Edinburgh, United Kingdom)
Background: The research interests of the groups centre on the immunobiology of the human malaria parasite, Plasmodium falciparum with a particular focus on the blood stage form that causes the disease. One of the main thrusts of our research at present is on the development of vaccines, based on recombinant surface proteins derived from genes expressed by the merozoite stage of the parasite life cycle. Much of this work is focused on merozoite surface protein 1 (MSP-1), but there are several merozoite proteins that may be the target of protective antibodies, including some previously uncharacterised proteins initially identified from proteome and genomic approaches. We examine the development of antibody responses to specific proteins of the malaria parasite in naturally exposed individuals, including studying the associations between specific responses and protection against clinical malaria episodes. This sero-epidemiological approach is supplemented by examining the functional activity of specific antibodies in parasite growth inhibition assays in vitro and studies on the role of the proteins in the interaction between parasite and host cell.
Aim of the project: The project is to identify and evaluate new and partially characterised proteins that may be the target of protective antibodies.
Methods: The work will include gene cloning and expression in recombinant form of candidate proteins that will be purified and used to develop functional assays. These assays will include measurement and functional analysis of both naturally acquired antibodies and antibodies raised by immunization, as well as binding assays to study the interaction between individual proteins and other parasite or host components. Studies on human parasite proteins may be supplemented with parallel studies on the corresponding protein in a rodent model.
Expected outcome: The intention is to develop new candidates to be evaluated as malaria vaccine components.
References:
1. Cavanagh, DR, Dodoo, D, Hviid, L, Kurtzhals, JA, Theander TG, Akanmori, BD, Polley, SD, Conway, DJ, Koram, K, and McBride, JS. (2004). Antibodies to the N-terminal block 2 of Plasmodium falciparum merozoite surface protein 1 are associated with protection against clinical malaria. Infect Immun72:6492-6502.
2. Conway, D. J., Cavanagh, D. R., Tanabe, K., Roper, C., Mikes, Z. S., Sakihama, N., Bojang, K. A., Oduola, A. M. J., Kremsner, P. G., Arnot, D. E., Greenwood, B. M., and McBride, J. S.(2000)A principal target of immunity to malaria identified by molecular population genetic and immunological analysis. Nature Medicine6: 689-692.
3. Cavanagh, D.R., I.M. Elhassan, C. Roper, V.J. Robinson, H. Giha, A.A. Holder, L. Hviid, T.G. Theander, D.E. Arnot, and J.S. McBride (1998) A longitudinal study of type-specific antibody responses to Plasmodium falciparum merozoite surface protein-1 in an area of unstable malaria in Sudan. Journal of Immunology161: 347-359.
4. Pachebat, J. A., Kadekoppala, M., Grainger, M., Dluzewski, A. R., Gunaratne, R. S., Ogun, S. A., Ling, I. T., Scott-Finnigan, T. J., Bannister, L. H., Taylor, H. M., Mitchell, G. H. and Holder,A.A. (2007) Extensive proteolytic processing of the malaria parasite Merozoite Surface Protein 7 during biosynthesis and parasite release from erythrocytes. Mol Biochem Parasitol., 151(1):59-69. Epub 2006 Nov 2
5. Green, J.L., L. Hinds, M. Grainger, E. Knuepfer and A. A. Holder (2006). Plasmodium thrombospondin related apical merozoite protein (PTRAMP) is shed from the surface of merozoites by PfSUB2 upon invasion of erythrocytes. Mol Biochem Parasitol. 150(1):114-117 Epub 2006 Jul 17
6. O’Keeffe, A. H., J. L. Green, M. Grainger and A. A. Holder (2005) A novel Sushi domain-containing protein of Plasmodium falciparum. Mol. Biochem. Parasitol. 140: 61-68